Synopsis

In this study a CO₂-challenge was applied to test the effect of amyloid deposition in HCHWA-D, a hereditary form of cerebral amyloid angiopathy (CAA), on the cerebrovascular reactivity (CVR). With dual echo arterial spin labeling, providing cerebral blood flow (CBF) and BOLD images, the CVR was measured in grey and white matter and the CO₂-challenge was evaluated as a whole brain biomarker. The effect of the CO₂-challenge was best measured with CBF in the grey matter. Future research should prove whether it is sensitive enough to detect treatment induced changes in (pre-)symptomatic CAA patients.

Introduction

In cerebral amyloid angiopathy (CAA) the toxic protein amyloid accumulates in the arterial and arteriolar vessel walls in the brain and is accompanied by degeneration of medial smooth muscle cells¹. Sporadic CAA has a high prevalence in the general elderly population with a prevalence of 80% in the oldest elderly and in patients with Alzheimer’s Disease (AD)². Provocation of neuronal activation by a visual task has been proposed to detect microvascular impairment in CAA. However, per definition, the effect of a visual stimulus is limited to the visual cortex. Alternatively, a CO₂-challenge can be used to probe the functioning of the (micro)vascular bed with the advantage of covering the entire brain.

Hereditary cerebral hemorrhage with amyloidosis, Dutch-type (HCHWA-D), is an autosomal dominant type of CAA causing lobar hemorrhages and hemorrhagic infarcts at an early age of approximately 50^3,4. HCHWA-D is considered to be a useful model to study sporadic CAA, since it allows for studying pure CAA independent of other age-related pathology and DNA-analysis can prove the presence of the condition, allowing early (pre-symptomatic) stages of the disease. Previously, it has been shown that the BOLD-response upon visual activation is already impaired in the pre-symptomatic HCHWA-D patient⁷.

The aim of this study was to assess cerebrovascular reactivity in HCHWA-D patients using a CO₂-challenge as a whole brain biomarker.

Methods

Eleven HCHWA-D patients with a genetic-based diagnosis of the presence of the amyloid precursor protein codon 693-mutation and one or more clinically and radiologically confirmed intracerebral hemorrhage(s), as well as eleven age and gender-matched healthy controls (Table 1), were scanned on a 3T Philips Achieva scanner using a 32-channel head-coil. This study was approved by the local Institutional research board, and participants provided written informed consent prior to inclusion.

Dual-echo pseudo-continuous arterial spin labeling (DE-ASL) scans were acquired with 17 slices at a 2.75x2.75x7mm³ resolution (multi-slice single-shot two-dimensional EPI read-out), see figure 1A. ASL images acquired at the first echo time (9.2ms) are perfusion (cerebral blood flow, CBF) weighted, whereas the second echo time (30ms) is primarily T₂*-weighted, thus sensitive to the BOLD signal⁶. A block-design CO₂-inhalation paradigm (2 minutes alternating normocapnia/hypercapnia by inhalation of 5% CO₂, 21% O₂ and 74% N₂ delivered through a non-rebreathing face mask, 10 minutes in total), applied with custom build gas-mixer was employed to target the (micro)vascular bed function over the whole brain, see figure 1B.

A 3D-anatomical (1mm isotropic) and M₀-scan were acquired for post-processing and CBF-quantification⁷. DE-ASL images were motion corrected and registered to an MNI-standard brain in FSL. Grey and white matter masks were segmented from the T₁-weighted images using FAST. End-tidal CO₂ (etCO₂) was recorded to correct for delays. Cerebrovascular reactivity (CVR) was calculated as: $$\text{CVR = }100\text{%}\times\frac{\text{hypercapnic MR signal}-\text{baseline MR signal}}{\text{baseline MR signal}\times\left(\text{hypercapnic etCO}_{2}-\text{baseline etCO}_{2}\right)}$$

Results

Discussion

Conclusion

Acknowledgements

This study was part of the CAVIA project (nr. 733050202), which has been made possible by ZonMW. The CAVIA project is part of ‘Memorabel’, the research and innovation programme for dementia, as part of the Dutch national ‘Deltaplan for Dementia’. The CAVIA project is a consortium of Radboudumc, LUMC, Erasmus MC, VUmc, ADX Neurosciences, Philips Healthcare, Stony Brook University and Massachusetts General Hospital.

References

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